Knowledge of the patterns and rates of background substitution is essential for the identification and analysis of functional sequences in the human genome. Provided this knowledge it should be possible to identify functional sequences in comparison of two or more genomes. Such sequences will stand out as those that have changed either significantly less or significantly more than expected under the estimated rates of background substitution. Despite this central importance, patterns of background substitution are poorly known. Questions of whether rates of background substitution vary across the human genome and whether these rates have been evolving in the human lineage remain controversial. Major difficulties lie in identifying sequences that evolve under no functional constraint and also in devising methods of inferences given the existence of a rapid neighbor-dependent CpG to TpG/CpA transition prevalent in mammalian DNA. The high rate and the neighbor-dependence of this process substantially complicate all inferences of substitution, even those of single-nucleotide substitutions at non-CpG sites. This project will utilize a new maximum likelihood method capable of simultaneous inference of the rates of CpG to TpG/CpA transition and of the rates of single-nucleotide substitution significantly beyond the point of naive saturation. This method will be applied to the abundant sequences of dead copies of transposable elements in the human and other mammalian genomes deposited over the last 200-300 million years. This analysis will provide essential new information regarding the evolution of patterns of substitution in mammalian genomes, will create fine-scale (1-5 Mbp) genomic maps of substitution patterns and rates of the human and other mammalian genomes, and will investigate genomic determinants of background substitution patterns in mammals.